The Role of ABC Transporters in Protecting Cells from Bilirubin Toxicity

The ATP-Binding Cassette (ABC) superfamily is the largest transporter family known to translocate a wide variety of exogenous and endogenous substrates across cell membranes. In this chapter we review the potential role of three ABC proteins in the transport of unconjugated bilirubin (UCB). These transporters are MRP1, MRP3 and PGP (MDR1). MRP1 is expressed at high levels in most epithelia, usually at the basolateral membrane. Among a multiplicity of substrates, MRP1 mediates the ATP-dependent cellular export of UCB, and its role has been demonstrated in protecting cells from UCB toxicity. MRP3 is an organic anion transporter whose major substrates are GSH conjugates of organic compounds. Among the MRP family members, MRP3 shares the highest degree of amino acid homology with MRP1. Although the hepatic expression of MRP3 has been reported to be up-regulated by bilirubin and bilirubin glucuronides, it is unknown whether MRP3 is also involved in the transport of UCB. PGP is expressed in organs involved in the elimination of endo-and xenobiotics and UCB is one of these substrates. Since the Km of PGP for UCB is well above pathophysiological levels of Bf, it remains uncertain whether it has a role in protecting against UCB cytotoxicity.